HCV (Hepatitis C virus) is a major cause of chronic liver disease. Hepatitis C virus is most commonly transmitted through exposure to contaminated blood. Due its widespread nature and global burden, this disease has always attracted attention for insight into its causative agent hepatitis C virus (HCV) and for the development of new therapeutic approaches. Even after twenty-four years from its discovery, HCV continues to be a major cause of concern and a huge burden on public health systems worldwide. WHO estimates that a minimum of 3% of the world's population is chronically infected with HCV. As cited in various research articles, HCV has caused massive impact on public health, and around 180 million people in the world are infected with HCV, with an estimated 3 to 4 million new infections global per year. It causes infection in two phases, first involves acute attack that last for few weeks; if untreated HCV may persist for long time which is termed as chronic hepatitis C. This chronic infection may often lead to chronic liver disease (CLD) that may ultimately lead to hepatic failure and hepato-cellular carcinoma.
The HCV virion is an enveloped positive-strand RNA virus with a single oligoribonucleotide genomic sequence of about 9600 bases which encodes a polyprotein of about 3,010 amino acids. The protein products of the HCV gene consist of the structural proteins C, E1, and E2, and the non-structural proteins NS2, NS3, NS4A and NS4B, and NS5A and NS5B.
The main targets of the direct-acting antiviral agents are the HCV-encoded proteins that are vital to the replication of the virus. The infectious viral structure is comprised of envelope glycoproteins in a lipid bilayer that contain the viral core protein and RNA. After cell entry, the viral RNA is translated through host machinery into a polyprotein, which is cleaved during and after translation by both host and viral-encoded proteases into 10 mature viral proteins, including a number of nonstructural (NS) proteins. One of the viral proteases involved in this post-translational processing is a heterodimeric complex of the NS3 and NS4A proteins (NS3/NS4A). NS3 possesses the proteolytic activity and NS4 is a membrane protein that acts as a cofactor. Synthesis of new viral RNA occurs in a highly structured replication complex that consists of NS3, NS4A, NS4B, NS5A, and NS5B. NS5B is an RNA-dependent RNA polymerase that is essential for viral replication. NS5A has a presumptive role in the organization of the replication complex and in regulating replication. It is also involved in assembly of the viral particle that is released from the host cell. Direct-acting antivirals are inhibitors of the NS3/4A protease, the NS5A protein, and the NS5B polymerase.
HCV is characterized by an extremely high degree of variability. The genetic heterogeneity of HCV leads to multiple genomic variants allowing rapid selection of mutants that better adapts to environmental changes. This genetic heterogeneity is the basis of chronic infection which leads to limited treatment efficacy. The various available options for the treatment of hepatitis C are screening, surgery, liver transplant, radiation therapy, chemotherapy, virus therapy and targeted therapy. A number of potential molecular targets for drug development of direct-acting antivirals (DAAs) as anti-HCV therapeutics have now been identified including, but not limited to, the NS2-NS3 autoprotease, NS4A protease, the N3 protease, the N3 helicase, and the NS5B polymerase.
Currently approved standard of care (“SOC”) for the treatment of chronic HCV infection is a combination therapy with pegylated interferon alfa-2a or pegylated interferon alfa-2b (collectively “peginterferon” or “PEG”) used alone or in combination with ribavirin (“RBV”). Other FDA approved drugs for hepatitis C include Olysio® (simeprevir), Victrelis® (boceprevir), Sovaldi® (sofosbuvir), Epclusa (Sofosbuvir; Velpatasvir)®, Viekirax® (dasabuvir, ombitasvir, paritaprevir, ritonavir), Daklinza® (daclatasavir), Exviera® (dasabuvir), Harvoni® (Ledipasvir Sofosbuvir), Incivek® (telaprevir), Technivie® (ombitasvir; paritaprevir; ritonavir) Zepatier® (elbasvir; grazoprevir), Viekira Pak® (dasabuvir sodium; ombitasvir; paritaprevir; ritonavir) etc.
Challenges facing current treatment of HCV include lack of efficacy in patients with difficult-to-treat disease, such as patients with cirrhosis or infected with HCV genotype 1 (who represent a majority of US HCV infections), the toxicity of combination therapy, the difficulty of therapy, and the poor reception of these treatments by many patients. Moreover an attempt to invent new drugs for the treatment of HCV would be costly and time consuming. Thus, there is a need for new treatments and therapies for HCV infection to treat or ameliorate one or more symptoms of Hepatitis C. Accordingly, the current invention focuses on the existing pool of drugs which could be effective in the treatment of Hepatitis C with the ultimate goals of targeting the virus, viral resistance challenges, shortening the length of therapy, improving sustained virologic response rates, and minimizing side effects.